Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells

By Jihye Yun, C. Rago, I. Cheong, R. Pagliarini, P. Angenendt, H. Rajagopalan, Kerstin Schmidt, James K. V. Wilson, S. Markowitz, Shibin Zhou and 6 more. Science, 2009

936 citations recorded by the source corpus.

Desperately Seeking Glucose Mutations in oncogenes and tumor suppressor genes allow cancer cells to outgrow their neighboring healthy cells. What microenvironmental conditions provide a selective growth advantage to these cells? Yun et al. (p. 1555, published online 6 August) identify low glucose availability as a microenvironmental factor driving the acquisition of KRAS oncogenic mutations that allow cancer cells to survive and grow. In genetically matched colorectal cancer cells that differed only in the mutational status of the KRAS oncogene, mutant cells selectively overexpressed glucose transporter-1 and exhibited enhanced glucose uptake and glycolysis. When cells with wild-type KRAS were placed in a low-glucose environment, very few cells survived but most of the survivors expressed high levels of glucose transporter-1, and a small percentage of the survivors had acquired new KRAS mutations. Thus, glucose deprivation may help to drive the acquisition of cell growth–promoting oncogenic mutations during tumor development. Glucose deprivation can drive the acquisition of certain oncogenic mutations in human cancer cells. Tumor progression is driven by genetic mutations, but little is known about the environmental conditions that select for these mutations. Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, we found that GLUT1, encoding glucose transporter-1, was one of three genes consistently up-regulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wild-type KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Together, these data suggest that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/bbca8eeafe8c96382b0288e0cd863d1fd61f802f

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In Cancer Research

1. Ralph J. Deberardinis
2. Navdeep S. Chandel
3. C. V. Dang
4. Craig B. Thompson
5. M. V. Vander Heiden
6. Patrick S. Ward
7. B. Faubert
8. Lewis C. Cantley

In Molecular Biology

1. Ralph J. Deberardinis
2. Navdeep S. Chandel
3. C. V. Dang
4. Craig B. Thompson
5. M. V. Vander Heiden
6. Lewis C. Cantley
7. Patrick S. Ward
8. B. Faubert

In Oncology

1. Ralph J. Deberardinis
2. Craig B. Thompson
3. C. V. Dang
4. Olivier Elemento
5. Lewis C. Cantley
6. Navdeep S. Chandel
7. M. V. Vander Heiden

Citations in the corpus

• Fundamentals of cancer metabolism (2016, background): “Some activities first become essential very early in tumorigenesis as the nascent tumor begins to experience nutrient limitations (6).”
• Otto Warburg's contributions to current concepts of cancer metabolism (2011, background): “It was recently reported that depriving colon carcinoma cells of glucose increases the mutation rate of RAS, which, thus activated, facilitates glucose import through induction of GLUT1 (also known as SLC2A1), an important glucose transporte”
• KRAS: feeding pancreatic cancer proliferation (2014, neutral): “Semenza GL. HIF-1: upstream and downstream of cancer metabolism.”
• Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. (2011, neutral): “RAS, another oncogene widely implicated in human cancer, also promotes glucose metabolism by enhancing glucose uptake (Yun et al 2009).”
• Metabolic reprogramming and cancer progression (2020, background): “Furthermore, simply culturing wild-type cells in low-glucose conditions selects for cells with enhanced GLUT1 expression, including clones that spontaneously acquire KRAS mutations (37).”
• Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH (2015, background): “Given that cancer cells with KRAS or BRAF mutations are heavily dependent on glycolysis for survival and growth and that pyruvate, the end product of glycolysis, is a major carbon source for the mitochondrial TCA cycle (7, 21), we hypothesized that inhibition of glycolysis at GAPDH might deplete ATP”
• Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “Yun et al. (2009) showed that depriving colon carcinoma cells of glucose increased the rate at which activating mutations in Ras grew out.”